Pharmaceutical inhalation compositions

ABSTRACT

A non-pressurized pharmaceutical inhalation composition includes a therapeutically effective amount of a particulate inhalation medicament. The medicament has a mass median diameter in the range 0.01 to 15 μm. A particulate polysaccharide entrapped flavoring agent is included in the composition and has a mass median diameter in the range of 10 to 200 μm. The composition can be used to practice a method for treatment of reversible obstructive airway disease which includes administering the pharmaceutical composition to a patient.

This invention relates to pharmaceutical compositions for administrationby inhalation, more particularly to non-pressurised powder compositions.

Many medicaments, especially those for the treatment of diseases of therespiratory tract, are administered by inhalation. However, somemedicaments, such as reproterol hydrochloride, have an undesirable tastewhen administered by inhalation, this being due to that proportion ofmedicament which is; deposited in the mouth and throat of the patient.Thus, it would be desirable to modify the taste of inhalationcompositions by incorporating a flavouring agent, as this may result inimproved patient compliance especially if the patients are youngchildren.

Medicaments for inhalation are commonly administered in the form ofpowders, either from pressurised canisters containing the powder inadmixture with a liquefied gas aerosol propellant, or as non-pressuriseddry powder compositions.

In the former case it is known to include flavouring and/or sweeteningagents in the composition to improve the taste of the composition and/orto give the composition a recognisable flavour so that the patientrealises when a dose has been inhaled, as disclosed in EP-A-365119.However, such compositions suffer from the disadvantage that thepropellant may comprise a chlorofluorocarbon (CFC) which is thought tobe harmful to the environment generally and the ozone layer inparticular. Furthermore, the flavouring agent may be inhaled into thelung.

It would be desirable to incorporate flavouring agents intonon-pressurised dry powder pharmaceutical compositions. However,flavouring agents usually exist as oils or sticky solids at roomtemperature. This renders them unsuitable for use in dry powderformulations, for example, because they have poor flow properties andcould cause the powdered medicament to agglomerate thus reducingdispersion to the lung.

We now provide a pharmaceutical inhalation composition which overcomesor substantially mitigates these disadvantages.

We have now found that by entrapping the flavouring agent in apolysaccharide, the flavouring agent may be kept sufficiently freeflowing to be incorporated into non-pressurised powder inhalationcompositions.

Thus, according to the invention, we provide a non-pressurisedpharmaceutical inhalation composition comprising a therapeuticallyeffective amount of a particulate inhalation medicament having a massmedian diameter in the range 0.01 to 15 μm and a particulatepolysaccharide entrapped flavouring agent having a mass median diameterin the range 10 to 200 μm.

Polysaccharide entrapped flavouring agents are known for use in the foodindustry. In addition to the flavouring agent and polysaccharide, foodflavourings generally contain other excipients, for example emulsifyingagents, e.g. acacia gum which is the gummy exudate from the stem andbranches of Acacia senegal and other species of Acacia. However, we havefound that the presence of excipients, such as emulsifying agents, maycause the polysaccharide entrapped flavouring agent to be sticky orotherwise render it unsuitable for use in non-pressurised pharmaceuticalinhalation compositions. Therefore, we prefer the particulatepolysaccharide entrapped flavouring agents used in the compositionsaccording to the invention to contain a minimum amount of, andpreferably no, excipients in addition to the flavouring agent andpolysaccharide.

Any conventional pharmaceutically acceptable flavouring agents may beused, particular flavouring agents which may be mentioned includevolatile oils, e.g. peppermint oil; and menthol. The proprietary productknown by the tradename DENTOMINT™ flavouring agent, which contains bothpeppermint oil and menthol, may also be used. We prefer the flavouringagent to be peppermint oil BP/Ph. Eur.

Polysaccharides in which the flavouring agent is entrapped include, forexample, polyglucoses. We prefer the polysaccharide to be a dextran or adextrin. We particularly prefer the polysaccharide to be a dextrin,especially maltodextrin. Dextrins such as maltodextrin may be preparedfrom a variety of sources, such as starches, e.g. maize, corn, wheat,rice, rye, oats, pea, tapioca or potato starch.

The molecular weight of the polysaccharide must be high enough to ensureadequate entrapment of the flavouring agent. The molecular weight mayvary, but is preferably from 500 to 1,000,000, more preferably from 500to 250,000, and especially from 500 to 20,000.

The flavouring agent may be entrapped in the polysaccharide byatomisation of a mixture of a solution of the polysaccharide and theflavouring agent. Any suitable form of atomiser can be used. Atomisationresults from an energy source acting on liquid bulk. Resultant forcesbuild up to a point where liquid break-up and disintegration occurs andindividual spray droplets are created. The different atomisationtechniques available concern the different energy forms applied to theliquid bulk. Common to all atomisers is the use of energy to break-upliquid bulk. Centrifugal, pressure and kinetic energy are used in commonforms of atomiser. Sonic and vibratory atomisers are also used. Specificatomisers which may be mentioned include rotary atomisers, e.g. thoseinvolving veined wheels, vaneless discs, cups, bowls and plates;pressure atomisers, e.g. those involving pressure nozzles, centrifugalpressure nozzles, swirl chambers and grooved cores; kinetic energy orpneumatic atomisers, e.g. those involving two or three fluids, orinternal or external mixing; and sonic energy nozzles, e.g. involvingsirens or whistles.

The atomiser can be used in a spray or flash drying apparatus, or spraycoagulation apparatus. More details of methods of spray drying etc maybe obtained from, for example, The Theory and Practice of IndustrialPharmacy, 3^(rd) Edition, Ch.3, p.61, and Ch.13, p.426, Ed: L. Lachman,H.A. Lieberman and J.L. Kanig, Lea & Febiger, 1986, Philadelphia; andSpray Drying Handbook, 5^(th) Edition, K. Masters, Longman Scientific &Technical 1991; and references therein.

The conditions of operation of the apparatus and storage of the solution(e.g. pH and temperature) should clearly not be such as to degrade theflavouring agent, or introduce impurities, or biological contamination,into the polysaccharide entrapped flavouring agent.

The polysaccharide entrapped flavouring agents used in the compositionsaccording to the invention preferably contain up to 50%, more preferablyup to 30%, e.g. 10 to 25% w/w flavouring agent, as measured by steamdistillation [British Pharmacopoeia (1988) Appendix 11, Test E: VolatileOil in Drugs].

The particulate polysaccharide entrapped flavouring agent having a massmedian diameter (MMD) in the range 10 to 200 μm has a size distributionsuch that the delivery of flavouring agent to the lung is minimised anddelivery of flavouring agent to the mouth is maximised. We prefer theparticulate flavouring agent to have a MMD in the range 10 to 100 μm. Weparticularly prefer the particulate flavouring agent to have a MMD ofgreater than 20 μm, e.g. 20 to 70 μm. We prefer less than 5% w/w, andmore preferably less than 2% w/w, of the particulate flavouring agent tohave a particle size of less then 10 μm. The operating conditions of theatomisation process used to produce the particulate flavouring agent maybe controlled so as to produce the desired particle size distribution,alternatively the flavouring agent may be sieved or otherwise classifiedafter production, using for example an "Alpine" Air-Jet Sieve, in orderto obtain the desired particle size distribution.

The mass median diameter, as is known by those skilled in the art, isdefined such that 50% by mass of the particulate material is in the formof particles having a s smaller diameter. Throughout this specification,the term is used to indicate the mass median diameter as determined bylaser diffraction light scattering techniques. The use of other methodsof particle sizing may give results which differ somewhat from thoseobtained by the light scattering technique. Other suitable methods ofparticle sizing will be well known to those skilled in the art andinclude microscopy and sedimentation. More details of methods ofparticle size determination may be obtained from, for example, TheTheory and Practice of Industrial Pharmacy, 3^(rd) Edition, Ch.2, p.21,Ed: L. Lachman, H.A. Lieberman and J.L. Kanig, Lea & Febiger, 1986,Philadelphia, and references therein.

The amount of particulate polysaccharide entrapped flavouring agentpresent in the compositions according to the invention will obviouslydepend upon the ability of the flavouring agent to mask the taste of theparticular active ingredient employed. However, in general, we preferthe compositions to comprise up to 25% w/w, preferably up to 10% w/w,e.g. 1 to 10% w/w; and more preferably up to 5% w/w, e.g. 1 to 5% w/w,of particulate flavouring agent.

In addition to the particulate flavouring agent the formulationsaccording to the invention may also contain other ingredients such assweetening agents or colourants. Any conventional sweetening agents maybe used but we particularly prefer saccharin sodium, mannitol,aspartame, cyclamates or sugar. When the formulation also contains otheringredients such as a sweetening agent, it may be spray dried into thepolysaccharide or mixed with a solution of the polysaccharide beforespray drying. Alternatively, if a solid form of a sweetening agent isused it may be admixed with the composition during formulation.

We prefer that at least 80% by weight and preferably more than 90%, ofthe inhalation medicament particles for use in the compositionsaccording to the invention are of less than 20 μm, more preferably ofless than 10 μm, and especially of less than 7 μm in diameter. Weparticularly prefer at least 80% of the particles to be from 2 to 15 μmin diameter.

The particulate inhalation medicaments may be prepared by any suitabletechnique, as will be known by those skilled in the art, suitabletechniques include milling, using e.g. a hammer mill, micronisation,spray drying and freeze drying.

Medicaments for use in the compositions according to the inventioninclude any medicaments which are conventionally administered byinhalation. Such medicaments include drugs for use in the prophylacticor remedial treatment of reversible obstructive airways disease.Specific medicaments which may be mentioned include salts of cromoglycicacid, e.g. sodium cromoglycate; salts of nedocromil, e.g. nedocromilsodium; inhaled steroids such as beclomethasone dipropionate, tipredane,budesonide and fluticasone; anticholinergic agents such as ipratropiumbromide; bronchodilators, e.g. salmeterol, salbutamol, reproterol,terbutaline, isoprenaline and fenoterol, and salts thereof; enzymes;vitamins and antihistamines. If desired a mixture of medicaments, forexample a mixture of sodium cromoglycate and a bronchodilator, such asisoprenaline, terbutaline, fenoterol, reproterol or a salt of any onethereof, may be used. We particularly prefer the medicament to be amixture of sodium cromoglycate and reproterol hydrochloride.

The invention may be particularly useful for medicaments which haveunpleasant tastes and/or aromas, or which have no discernable taste oftheir own.

According to a further aspect of the present invention we provided amethod of treatment of reversible obstructive airways disease, whichmethod comprises administration to a patient suffering from orsusceptible to such a condition of a pharmaceutical compositioncomprising a therapeutically effective amount of a particulateinhalation medicament having a mass median diameter in the range 0.01 to15 μm and a particulate polysaccharide entrapped flavouring agent havinga mass median diameter in the range 10 to 200 μm.

The pharmaceutical compositions according to the invention willgenerally be manufactured in a form suitable for direct administrationto a patient. For example, the compositions may comprise the particulateinhalation medicament and flavouring agent in admixture with a solidpharmaceutically acceptable carrier. The carrier preferably has aneffective particle size of from 30 to 120 μm.

The term "effective particle size" is used to denote the apparentparticle size of a body without distinction as to the number ofindividual particles which go to make up that body i.e. no distinctionis made between a single particle of given size and an agglomerate ofthe same size which is composed of finer individual particles.

The solid pharmaceutically acceptable carrier in the composition willgenerally be a non-toxic material chemically inert to the inhalationmedicament but may, if so desired, also comprise larger particles of theinhalation medicament. Examples of carriers which may be used in thecomposition include a dextran, mannitol and, preferably, lactose. Aparticularly preferred carrier is crystalline lactose.

The particles of carrier preferably have a mass median diameter of fromabout 30 to 150 μm. The mass median diameter is preferably less than 100μm and more preferably less than 80 μm. It is particularly preferredthat the mass median diameter of the carrier particles be in the range30 to 80 m, e.g. about 50 to 60 μm.

When the composition is in admixture with a solid carrier, we prefer thecontent of the inhalation to be from 0.1 to 70% w/w, more preferablyfrom 0.1 to 55% w/w, and especially from 5 to 50% w/w.

Therefore, according to a further, preferred aspect of the inventionthere is provided a pharmaceutical inhalation composition comprising 0.1to 70% w/w of a particulate inhalation medicament having a mass mediandiameter in the range 0.01 to 15 μm and 0.1 to 10% w/w of particulatemaltodextrin entrapped peppermint oil having a mass median diameter inthe range 10 to 200 μm, in admixture with a solid pharmaceuticallyacceptable carrier having an effective particle size of from 30 to 120μm.

The particulate carrier may be prepared by grinding the carrier andsubsequently separating out the desired fraction by conventionalmethods, e.g. by air classification and sieving.

The composition may be prepared by mixing the ingredients together in amixer, e.g. a planetary or other stirred mixer. The invention thus alsoprovides a method for preparing a composition according to the inventionwhich comprises mixing together the particulate inhalation medicament,the particulate flavouring agent and the solid carrier, aftercomminution and particle size classification of the ingredients if thisis necessary. The technique of Differential Scanning Calorimetry may beused to illustrate the chemical compatibility of the various componentsof the compositions according to the invention upon storage.

The compositions according to the invention may also be formulated as aso-called "pelletised" composition, i.e. as soft pellets of diametergreater than 30 μm, each pellet comprising a plurality of individualparticles loosely held together such that upon inhalation the pelletsdisintegrate to the constituent particles. Pelletised compositions maybe prepared according to the method described in GB 1520247. When thecomposition is in the form of, e.g. soft pellets, we prefer the contentof the inhalation medicament to be from 5 to 99% w/w.

We prefer the compositions according to the invention to have adispersion of from 5 to 35%, preferably from 10 to 35%, more preferablyfrom 20 to 35% as measured by apparatus B as specified in the BritishPharmacopoeia (1988).

The particular formulation and method of putting up the compositionsaccording to the invention will, of course, depend upon the nature ofthe inhalation device intended for administration of the composition.

The compositions according to the invention may be put up in unit doseform, for example, in gelatine, plastics or other capsules; or in ablister pack as disclosed in GB 2169265 or GB 2246299.

Compositions put up in capsules may be administered from, e.g. thedevice known as SPINHALER™ (Fisons plc) inhalation device, andcompositions put up in blister packs may be administered from, e.g. thedevice disclosed in GB 2129691 or GB 2246299.

The amount of inhalation medicament contained in a unit dose will, ofcourse, to some extent depend on the desired dosage and the potency ofthe medicament, but will generally be from about 10μg to 50 mg, e.g. 20mg.

Therefore, according to a further aspect of the invention, we providepharmaceutical composition according to the invention in unit dose formcomprising from 10 μg to 50 mg of particulate inhalation medicament.

The compositions may also be put up in a multi-dose form, for example,in a cartridge, or a reservoir e.g. a hopper, intended to feed thedosing system of a multi-dose medicament inhalation device such as thatdisclosed in WO 91/13646.

We prefer the moisture content of the composition put up in this mannerto be sufficiently low for the powder to be free flowing. When thecomposition is intended for administration from, for example, a gelatinecapsule we prefer the moisture content to be sufficiently high toprevent the gelatine capsule from becoming brittle.

The compositions according to the invention may also be formulated asmedicament compacts, of the type disclosed in EP-A-407028. Thecompositions are surprisingly advantageous for formulation in thismanner since the polysaccharide entrapped flavouring agents aresufficiently resilient to sustain the compression forces required toproduce the medicament compacts without releasing the flavouring agententrapped therein to any significant extent.

The compositions according to the invention are advantageous in thatthey may mask or otherwise improve the taste of otherwiseunpleasant-tasting medicaments, or they may give the composition arecognisable flavour so that the patient realises when a dose has beeninhaled. In addition they may exhibit increased dispersion or increasedshelf-life when compared to compositions containing other or noflavouring agents. When then compositions according to the invention areput up into, for example, gelatin capsules, they may prevent the capsulebecoming brittle, or reduce moisture ingress in to the capsule ascompared to compositions containing other or no flavouring agents.

The invention is illustrated, but in no way limited, by the followingExamples.

EXAMPLE 1

    ______________________________________                                        Ingredients               % w/w                                               ______________________________________                                        Sodium cromoglycate (micronised)                                                                        47.06                                               Reproterol hydrochloride  3.53                                                Flavoured polyglucose     2.35                                                (85% maltodextrin:15% peppermint oil)                                         Lactose                   to 100                                              ______________________________________                                    

The medicaments, flavouring agent and carrier were each passed through a44 mesh sieve to remove or break up agglomerated particles, then mixedtogether using a high energy TURBULA™ mixer. The composition was thenput up into hard gelatine capsules each containing 20 mg of sodiumcromoglycate (measured as anhydrous) and 1.5 mg of reproterolhydrochloride.

EXAMPLE 2

    ______________________________________                                        Ingredients               % w/w                                               ______________________________________                                        Nedocromil sodium (milled)                                                                              50                                                  Flavoured polysaccharide  5                                                   (85% maltodextrin:15% peppermint oil)                                         Lactose                   to 100                                              ______________________________________                                    

The composition was put up into gelatine capsules each containing 10 mgof nedocromil sodium (measured as anhydrous material).

EXAMPLE 3

As for Example 2 but containing 10% w/w flavoured polysaccharide.

EXAMPLE 4

    ______________________________________                                        Ingredients               % w/w                                               ______________________________________                                        Nedocromil sodium (milled)                                                                              50                                                  Flavoured polysaccharide  5                                                   (85% maltodextrin:15% peppermint oil)                                         Saccharin sodium          1.25                                                Lactose                   to 100                                              ______________________________________                                    

The composition was put up into gelatine capsules each containing 10 mgof nedocromil sodium (measured as anhydrous material).

EXAMPLE 5

As for Example 4 but containing 10% w/w flavoured polysaccharide.

EXAMPLE 6

    ______________________________________                                        Ingredients               % w/w                                               ______________________________________                                        Nedocromil sodium (milled)                                                                              50                                                  Flavoured polysaccharide  5                                                   (85% maltodextrin:15% peppermint oil)                                         Lactose                   to 100                                              ______________________________________                                    

The ingredients were mixed according to the method of Example 1, thenmetered into the powder chamber of a device such as that disclosed inEP-A-407028. The powder was then compacted using a compression rig. Thecomposition when administered by a device as disclosed in EP-A-407028,delivers 6 mg of nedocromil sodium (measured as anhydrous material) peractuation.

The following compositions were prepared according to the method ofExample 6:

EXAMPLE 7

As for Example 6 but containing 10% w/w flavoured polysaccharide.

EXAMPLE 8

    ______________________________________                                        Ingredients               % w/w                                               ______________________________________                                        Nedocromil sodium (milled)                                                                              50                                                  Flavoured Polysaccharide  5                                                   (85% maltodextrin:15% peppermint oil)                                         Saccharin sodium          1.25                                                Lactose                   to 100                                              ______________________________________                                    

EXAMPLE 9

As for Example 8 but containing 10% w/w flavoured polysaccharide.

We claim:
 1. A non-pressurised pharmaceutical inhalation composition comprising a therapeutically effective amount of a particulate inhalation medicament having a mass median diameter in the range 0.01 to 15 μm and a particulate polysaccharide entrapped flavouring agent having a mass median diameter in the range 10 to 200 μm.
 2. A pharmaceutical composition according to claim 1, wherein the polysaccharide is a polyglucose.
 3. A pharmaceutical composition according to claim 2, wherein the polyglucose is maltodextrin.
 4. A pharmaceutical composition according to claim 1, wherein the particulate polysaccharide entrapped flavouring agent has a mass median diameter in the range 20 to 70 μm.
 5. A pharmaceutical composition according to claim 1, wherein the flavouring agent is peppermint oil.
 6. A pharmaceutical composition according to claim 1, which contains one or more medicaments selected from the group consisting of nedocromil sodium, reproterol hydrochloride and sodium cromoglycate.
 7. A pharmaceutical composition according to claim 1, in admixture with a solid pharmaceutically acceptable carrier.
 8. A pharmaceutical composition according to claim 7, wherein the pharmaceutically acceptable carrier is lactose.
 9. A pharmaceutical inhalation composition comprising 0.1 to 70% w/w of a particulate inhalation medicament having a mass median diameter in the range 0.01 to 15 μm and 0.1 to 10% w/w of particulate maltodextrin entrapped peppermint oil having a mass median diameter in the range 10 to 200 μm, in admixture with a solid pharmaceutically acceptable carrier having an effective particle size of from 30 to 120 μm.
 10. A pharmaceutical composition according to claim 1, in unit dose form comprising from 10 μg to 50 mg of particulate inhalation medicament. 